The present invention relates to novel anticancer agents, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The present invention more particularly relates to novel derivatives of andrographolide, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The novel derivatives of andrographolide have the general formula (I), 
where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms; R4 represents hydrogen, halogen or XR7 where X represents O, S, or NH and R7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, alkenoyl, alkanoyl, aroyl, heteroaroyl, aralkenoyl, aralkanoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94NHxe2x80x94R8 where R8 represents substituted or unsubstituted groups selected from alkyl, aryl, or aralkyl; with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group and (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl.
The andrographolide derivatives represented by general formula (I) as defined above and general formulas (X) and (XI) as defined below of the present invention are useful for treating cancer and other proliferative diseases including but not limited to herpes simplex virus types I and II (HSV I and HSV II) and human immunodeficiency (HIV). The compounds of the present invention are also useful in the treatment of psoriasis, restenosis, atherosclerosis and other cardiovascular disorders. The compounds of the present invention are also useful as antiviral, antimalarial, antibacterial, hepatoprotective, immunomodulating agents and for the treatment of metabolic disorders. The anticancer activity exhibited may be through cytotoxic activity, antiproliferation, cell cycle kinase inhibition or may be through cell differentiation.
The novel compounds of this invention are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, body weight reduction, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
The present invention also relates to pharmaceutical compositions containing compounds of general formula (I), formula (X), or formula (XI), or their stereoisomers, their polymorphs, their salts or their solvates or mixtures thereof.
The present invention also relates to a process for the preparation of the compounds of general formula (I), formula (X), and formula (XI), and their stereoisomers, their polymorphs, and their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates.
The plant andrographis paniculata is extensively used in medicine as a bitter tonic, febrifuge and in bowel complaints (Glossary of Indian Medicinal Plants., Ed. R. N. Chopra, S. L. Nayar, I. C. Chopra, p18, 1996. The useful plants of India, Ed. By S. B. Ambasta, p39, 1992). The plant is useful in the treatment of bacterial infections (Int. J. Crude Drug Res. 1990, 28(4), p273-283; Drugs of the Future. 1990, 15(8) p809-816). It is reported to possess antimalarial (Int. J. Pharmacognosy, 1992, 30(4), p263-274; J. Ethnopharmocol., 1999, 64(3), p249-254) and immunostimulant activity (J. Nat. Prod., 1993, 56(7), p995-999). The plant has also been shown to be antithrombotic (Chinese Medical Journal 1991, 104(9), p770-775) and inhibit stenosis and restenosis after angioplasty in the rat (Chinese Medical Journal, 1994, 107(6), p464-470). It is also known that the plant extract and its constituents exhibit promising hepatoprotective activity (Planta Medica, 1987, 53(2), p135-140). Significant attention has been paid by several research groups on A. paniculata in recent years due to its cytotoxic, antitumorogenic, cell differentiation inducing activities and anti-HIV activities.
Andrographolide having the formula (II), 
the major constituent of the plant A. paniculata was first isolated by Gorter (Rec. trav. chim., 1911, 30, p151-160). 
The extracts of the dried plant, which contains compounds of formula (III), have been assayed for the ability to decrease expression and phosphorylation of p34cdc2 kinase, cyclin B and c-Mos for treating or preventing pathogenecity of diseases such as AIDS, Alzheimer""s disease and hepatitis (WO 96/17605).
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Progress in Cell Cycle Research, 1995, 1, p351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1, cdk2, cdk4, cdk5, cdk6 and wee-1 kinase. Increased activity or temporarily abnormal activation of these kinases has been shown to result in development of tumors and other proliferative disorders such as restenosis. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner or by binding to and inactivating the kinase, cause inhibition of cell proliferation and are thus useful for treating tumors or other abnormally proliferating cells.
The extract of A. paniculata was found to show significant cytotoxic activity against KB and P388 cells. Interestingly, Andrographolide of the formula II, has been shown for the first time to have potent cytotoxic activity against KB as well as P388 lymphocytic leukemia, where as 14-deoxy-11,12-didehydroandrographolide and neoandrographolide having the formulae IV and V 
where R represents xcex2-D-glucose moiety, have shown no cytotoxic activity in tumor cell lines (J. Sci. Soc. Thailand, 1992, 18, p187-194).
The methanolic extract of the aerial parts of A. paniculata Nees showed potent cell differentiation inducing activity on mouse myeloid leukemia (M1) cells (Chem. Pharm. Bull. 1994, 42(6) 1216-1225).
Japanese patent application JP 63-88124, discloses a mixture of at least two compounds of formula VIa, VIb, 
where R1, R2, R3, R4 and R5 represent hydrogen or lower alkanoyl group and their activity as antitumorogenic agents.
DASM (dehydroandrographolide succinic acid monoester) prepared from andrographolide of the formula II is found to be inhibiting HIV virus and nontoxic to the H9 cell at the concentrations of 50-200 xcexcg/ml and was inhibitory to HIV-1 (EIB) at the minimal concentration of 1.6-3.1 xcexcg/ml (Proc. Soc. Exp. Biol. Med., 1991, 197, p59-66).
The plant Andrographis paniculata is also reported to inhibit proprotein convertases-1,-7 and furin possibly by suppressing the proteolytic cleavage of envelops glycoprotein gp 160 of HIV, which is known to be PC-mediated, particularly by furin and PC (Biochem. J, 1999, 338, 107-113)
In International patent application WO 91/01742, compositions containing one or more ingredients obtained from the plants Valeariana officinalis and/or A. paniculata were disclosed to have antiviral, antineoplastic, antibacterial and immunomodulatory activity.
Although several novel andrographolide derivatives have been prepared, screened and reported in the above said prior-art literature for their anticancer activity, they are not showing interesting activity.
With an objective of preparing novel andrographolide derivatives useful for treating cancer, infections and diseases caused by HSV, HIV, psoriasis, restenosis, atherosclerosis, cardiovascular disorders, also useful as antiviral, antimalarial, antibacterial, hepatoprotective, immunomodulating agents and for treatment of metabolic disorders, which are potent at lower doses and having better efficacy with lower toxicity, we focussed our research efforts in preparing the novel andrographolide derivatives of the formula (I) as defined above.
The main objective of the present invention is, therefore, to provide novel andrographolide derivatives of the formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and compositions containing them or their mixtures.
Another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates, or their mixtures in combination with one or more pharmaceutically acceptable active compounds with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Still another objective of the present invention is to provide a process for the preparation of novel andrographolide derivatives of the formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activity with little or no toxic effect or reduced toxic effect.
Accordingly, the novel derivatives of andrographolide of the present invention have the general formula (I) 
where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms; R4 represents hydrogen, halogen or XR7 where X represents O, S, or NH and R7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, alkenoyl, alkanoyl, aroyl, heteroaroyl, aralkenoyl, aralkanoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94NHxe2x80x94R8 where R8 represents substituted or unsubstituted groups selected from alkyl, aryl, or aralkyl; with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group and (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl; their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
Suitable groups represented by R1, R2 and R3 include hydrogen, substituted or unsubstituted, linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, furyl, thiophenyl and the like, the heteroaryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; heteroaralkyl group such as pyridylmethyl, pyridylethyl, furanmethyl, furanethyl and the like, the heteroaralkyl group may be substituted; (C2-C8) alkanoyl group such as ethanoyl, propanoyl, butanoyl and the like, the (C2-C8) alkanoyl group may be substituted; (C3-C8) alkenoyl group such as propenoyl, butenoyl, pentenoyl and the like, (C3-C8) alkenoyl group may be substituted; aroyl group such as benzoyl and the like, the aroyl group may be substituted; heteroaroyl group such as pyridyl carbonyl, furyl carbonyl and the like; the heteroaroyl group may be substituted; aralkenoyl group such as phenylpropenoyl, phenylbutenoyl, phenylpentenoyl and the like, the aralkenoyl group may be substituted; aralkanoyl group such as phenylpropanoyl, phenylbutanoyl, phenylpentanoyl and the like, the aralkanoyl group may be substituted; heteroaralkanoyl group such as pyridylethanoyl, pyridylpropanoyl, thiopheneethanoyl, thiophenepropanoyl and the like, the heteroaralkanoyl group may be substituted; heteroaralkenoyl group such as pyridylethenoyl, pyridylpropenoyl, thiopheneethenoyl, thiophenepropenoyl and the like, the heteroaralkenoyl group may be substituted; sulfonyl group such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and the like, the sulfonyl group may be substituted.
Suitable cyclic structures formed by OR2 and OR3 may be selected from xe2x80x94Oxe2x80x94(CR9R10)mxe2x80x94Oxe2x80x94 where R9 and R10 may be same or different and independently represent hydrogen, unsubstituted or substituted groups selected from (C1-C6) alkyl such as methyl, ethyl, n-propyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, furyl, thiophenyl, pyrrolyl and the like; the heteroaryl group may be substituted or R9 and R10 together represent Cxe2x95x90O; m represents an integer 1 or 2. The substituents on R9 and R10 include hydroxy, halogen such as fluorine, chlorine, bromine and the like; nitro, cyano or amino, (C1-C6)alkyl, (C1-C6)alkoxy, aryl or aroyl groups.
Suitable groups represented by R4 include hydrogen, halogen such as fluorine, chlorine, bromine and the like; or XR7 where R7 represents hydrogen or linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like, the alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; (C3-C8) alkenoyl group such as propenoyl, butenoyl, pentenoyl and the like, the alkenoyl group may be substituted; (C2-C8) alkanoyl group such as ethanoyl, propanoyl, butanoyl and the like, the alkanoyl group may be substituted; aroyl group such as benzoyl and the like, the aroyl group may be substituted; heteroaroyl group such as pyridyl carbonyl, furyl carbonyl and the like, the heteroaroyl group may be substituted; aralkenoyl group such as phenylpropenoyl, phenylbutenoyl, phenylpentenoyl and the like, the aralkenoyl group may be substituted; aralkanoyl group such as phenylpropanoyl, phenylbutanoyl, phenylpentanoyl and the like, the aralkanoyl group may be substituted; sulfonyl group such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and the like, the sulfonyl group may be substituted or a group xe2x80x94(CO)xe2x80x94NHxe2x80x94R8 where R8 represents linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like, (C1-C8)alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; or aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted.
Suitable groups represented by R5 include (C1-C6)alkyl such as methyl, ethyl, n-propyl and the like, the (C1-C6)alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; or aroyl group such as benzoyl and the like, the aroyl group may be substituted. The substituents on the alkyl group, aromatic moiety of the aryl group, aralkyl group or aroyl group include halogen atom such as fluorine, chlorine and bromine; amino group, cyano, hydroxy, nitro, trifluoroethyl, (C1-C6) alkyl, or (C1-C6) alkoxy.
Suitable groups represented by R6 include hydrogen, or substituted or unsubstituted (C1-C6) alkyl such as methyl, ethyl, n-propyl and the like. The substituents on the alkyl group include halogen atom such as fluorine, chlorine and bromine; amino group, cyano, hydroxy, nitro, trifluoroethyl, (C1-C6) alkyl, or (C1-C6) alkoxy.
The suitable substituents on R1, R2, R R7 and R8 may be selected from cyano, hydroxy, nitro, thio, halogen atom such as fluorine, chlorine, bromine and the like; or substituted or unsubstituted groups selected from linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like; amino, mono or disubstituted amino group; alkanoyl group such as ethanoyl, propanoyl, butanoyl and the like; thio(C1-C8)alkyl such as thiomethyl, thioethyl, thiopropyl and the like; (C1-C6)alkoxy group such as methoxy, ethoxy, propyloxy, butyloxy and the like; aroyl group such as benzoyl and the like; acyloxy group such as acetyloxy, propanoyloxy, butanoyloxy and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be mono or disubstituted; heteroaryl group such as pyridyl, furyl, thienyl and the like; acylamino groups such as CH3CONH, C2H5CONH, C3H7CONH, C4H9CONH and C6H5CONH; aralkylamino group such as C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3 and the like; alkoxycarbonylamino group such as C4H9OCONH, C2H5OCONH, CH3OCONH and the like; aryloxycarbonylamino group such as C6H5OCONH, C6H5OCONCH3, C6H5OCONC2H5, C6H4(CH3)OCONH, C6H4(OCH3)OCONH, and the like; aralkoxycarbonylamino group such as C6H5CH2OCONH, C6H5CH2CH2OCONH, C6H5CH2OCON(CH3), C6H5CH2OCON(C2H5), C6H4(CH3)CH2OCONH, C6H4(OCH3)CH2OCONH and the like; (C1-C8)alkylthio group such as methylthio, ethylthio, propylthio and the like; heteroarylthio group such as pyridylthio, furylthio, thiophenylthio, benzothiazolethio, purinethio, benzimidazolethio, pyrimidinethio and the like; acylthio group such as acetylthio, propanoylthio, butanoylthio and the like; aralkylthio group such as benzylthio, phenylethylthio, phenylpropylthio and the like; arylthio group such as phenylthio, napthylthio and the like; (C1-C8)alkylseleno such as methylseleno, ethylseleno, propylseleno, iso-propylseleno and the like; acylseleno such as acetylseleno, propionylseleno and the like; aralkylseleno such as benzylseleno, phenylethylseleno, phenylpropylseleno and the like; arylseleno such as phenylseleno, napthylseleno and the like or COOR, where R represents hydrogen or (C1-C6) alkyl groups. The substituents are selected from halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, aryl or (C1-C6)alkoxy groups.
When the groups R1, R2, R3, R5, R7 and R8 represent disubstituted aryl, the two substituents on the adjacent carbon atoms form a linking group such as xe2x80x94Xxe2x80x94CH2xe2x80x94Yxe2x80x94, xe2x80x94Xxe2x80x94CH2xe2x80x94CH2xe2x80x94Yxe2x80x94, where X and Y may be same or different and independently represent O, NH, S or CH2.
When the groups represented by R1, R2, R3, R5, R7 and R8 are multi substituted, the substituents present on the two adjacent carbons may form a linking group xe2x80x94Xxe2x80x94(CR11R12)nxe2x80x94Yxe2x80x94 where R11 and R12 represent (C1-C8)alkyl such as methyl, ethyl and the like, X and Y may be same or different and independently represent CH2, O, S, NH; and n=1 or 2.
Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,Nxe2x80x2-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,Nxe2x80x2-diphenylethylenediamine, N,Nxe2x80x2-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, serine, threonine, and phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
Particularly useful compounds according to present invention include:
3,19-Isopropylidene andrographolide;
3,19-Benzylidene andrographolide;
3,19-(1-Phenylethylidene)andrographolide;
3,19-Isopropylidene-14-(N-Boc methionyl)andrographolide;
14-Acetyl 3,19-methylenedioxy andrographolide;
14-Acetyl 3,19-O-cyclic carbonyl andrographolide;
14-Acetyl andrographolide;
14-Chloroacetyl andrographolide;
14-(Phenylcarbamoyl)andrographolide;
14-(N-Isopropyl carbamoyl)andrographolide;
14-Cinnamoyl andrographolide;
14-Isopropanoyl andrographolide;
14-Pivaloyl andrographolide;
14-Benzoyl andrographolide;
14-Benzyl andrographolide;
3,19-Diacetyl-14-(2xe2x80x2-acetyl-3xe2x80x2-acetamido 3xe2x80x2-phenyl)propionyl andrographolide;
3,19-Diacetyl-14-[4xe2x80x2S,5xe2x80x2R-(N-t-Butoxycarbonyl)-2xe2x80x2,2xe2x80x2-dimethyl-4xe2x80x2-phenyl-5xe2x80x2-oxazolidine]carbonyl andrographolide;
3,19-Diacetyl-14-(2xe2x80x2hydroxy-3xe2x80x2-benzoylamino 3xe2x80x2-phenyl) propionyl andrographolide;
3,19-Diacetyl-14-(2xe2x80x2hydroxy-3-N-Boc amino-3xe2x80x2-phenyl)propionyl andrographolide;
14-(N-Boc-glycinyl)-3,19-dipropionyl andrographolide;
14-(N-Boc-glycinyl)-3,19-diacetyl andrographolide;
14-(N-Acetylglycinyl)-3,19-diacetyl andrographolide;
14-(N-Benzoylglycinyl)-3,19-diacetyl andrographolide;
3,19-Diacetyl-14-O-ethyl andrographolide;
3,19-Diacetyl-14-O-methyl andrographolide;
3,19-Diacetyl-14-(3 ,4-dimethoxycinnamoyl)andrographolide;
14-(3,4-dimethoxy)cinnamoyl-3,19-dipropionyl-andrographolide;
3-Acetyl andrographolide;
3,14-Diacetyl andrographolide;
3,14,19,7-Tetra acetyl andrographolide;
3,19-Isopropylidene-14-acetyl andrographolide;
14-Chloroacetyl-3,19-isopropylidene andrographolide;. 14-Carbamoyl-3,19-isopropylidene andrographolide;
3,19-Isopropylidene-14-(N-isopropyl)carbamoyl andrographolide;
14-[4xe2x80x2S,5R-(N-t-butoxycarbonyl-2xe2x80x2,2xe2x80x2-dimethyl-4xe2x80x2-phenyl-5xe2x80x2-oxazolidine]carbonyl 3,19-isopropylidene andrographolide;
14-[4xe2x80x2S,5xe2x80x2R-(N-t-butoxycarbonyl-2xe2x80x2,2xe2x80x2-dimethyl-4xe2x80x2-phenyl-5xe2x80x2-oxazolidine]carbonyl andrographolide;
3,19-Isopropylidene-14-(N-Boc-glycinyl)andrographolide;
14-(N-Boc-glycinyl)andrographolide;
14-O-Ethyl-3,19-isopropylidene andrographolide;
14-O-Ethyl andrographolide;
14-O-Methyl-3,19-isopropylidene andrographolide;
14-O-Methyl andrographolide;
14-(3,4-Dimethoxy)cinnamoyl andrographolide;
19-Trityl andrographolide;
3-Acetyl-19-trityl andrographolide;
3,14-Diacetyl-19-trityl andrographolide and 7-Hydroxy-3,14,19-triacetyl andrographolide.
The present invention also provides a process for the preparation of novel andrographolide of the general formula (I), where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroalkenoyl, sulfonyl group or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms and R4 represents hydrogen; with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group, (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl; their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises: reacting the compound of formula (VII) 
with R1xe2x80x94L, R2xe2x80x94L and R3xe2x80x94L, where R1, R2 and R3 are as defined above and L represents hydroxy or a leaving group such as halogen atom like fluorine, chlorine, bromine or iodine; p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like; or an alkanoate such as acetate, propanoate, butanoate and the like, to produce a compound of formula (I), where all symbols are as defined earlier and R4 represents hydrogen.
The reaction of a compound of formula (VII) with R1xe2x80x94L, R2xe2x80x94L and R3xe2x80x94L, to produce a compound of formula (1) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In another embodiment of the present invention the compounds of formula (I) may also be prepared by a process, which comprises:
(i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups using conventional methods to produce a compound of formula (VIII), 
where R4 represents hydrogen; P1 and P2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like,
(ii) reacting the compound of formula (VIII) defined above with a compound of formula (IX)
R1xe2x80x94Lxe2x80x83xe2x80x83(IX)
where R1 and L have the meanings given above to produce a compound of formula (X), 
where R1, R4, P1 and P2 are as defined above,
(iii) deprotecting the compound of formula (X) by conventional methods to produce a compound of formula (XI), 
where R1 and R4 have the meanings given above,
(iv) reacting the compound of formula (XI) where R1 has the meaning given above with R2xe2x80x94L and/or R3xe2x80x94L, where R2 and R3 are as defined above to produce a compound of formula (I), and if desired,
(v) converting the compound of formula (I) into their stereoisomers, pharmaceutical salts by conventional methods.
The protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like. The reaction may be carried out in the presence of a suitable catalyst such as SOCl2, H2SO4, HClO4, pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like. The reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
The reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DLAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
The deprotection of a compound of formula (X) to produce a compound of formula (XI) may be carried out using deprotecting agent such as acetic acid, hydrochloric acid, formic acid, trifluoroacetic acid and the like. The reaction may be carried in the presence of a suitable solvent such as water, THF, dioxane, DCM, CHCl3, methanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
The reaction of compound of formula (XI) with R2xe2x80x94L and/or R3xe2x80x94L, to produce a compound of formula (I) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In another embodiment of the invention there is provided a process for the preparation of the compound of formula (I) where R4 represents XR7 where R7 and other symbols are as defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) converting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier to produce a compound of formula (XII), 
where all the symbols are as defined above, the compound of formula (XII) represents a compound of formula (I) when X represents O,
(ii) reacting the compound of formula (XII) with R7xe2x80x94L where R7 is as defined earlier, to produce a compound of formula (I).
Conversion of the compound of formula (I) to produce a compound of formula (XII) may be carried out in the presence of reagents such as SeO2, t-BuO2H, H2O2 and the like. The reaction may be carried out in the presence of solvents such as DCM, CHCl3, benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof. The temperature and duration of the reaction may be maintained in the range of 0 to 30xc2x0 C. and 3 to 48 h respectively.
The reaction of compound of formula (XII) with R7xe2x80x94L to produce a compound of formula (I) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In another embodiment of the invention there is provided a process for the preparation of the compound of formula (I) where R4 represents halogen and other symbols are as defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) converting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier to produce a compound of formula (XII), 
where all the symbols are as defined above, the compound of formula (XII) represents a compound of formula (I) when X represents O,
(ii) converting the compound of formula (XII) to a compound of formula (I), where R4 represents halogen atom such as fluorine, chlorine, bromine or iodine.
Conversion of the compound of formula (I) to produce a compound of formula (XII) may be carried out in the presence of reagents such as SeO2, t-BuO2H, H2O2 and the like. The reaction may be carried out in the presence of solvents such as DCM, CHCl3, benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof. The temperature and duration of the reaction may be maintained in the range of 0 to 30xc2x0 C. and 3 to 48 h respectively.
The conversion of compound of formula (XII) to compound of formula (I) may be carried out using halogenating agents such as thionyl chloride, thionyl bromide, phosphonyl chloride, PCl5, PBr3, bromine trifluoride, N-bromosuccinimide-hydrogen fluoride (NBS-HF), cobalt (III) fluoride, lithium fluoride, potassium fluoride, sodium fluoride, cesium fluoride, potassium iodide, sodium iodide, iodine, iodine cerium (IV) ammonium nitrate or R7xe2x80x94L where R7 and L are as defined above. The reaction may be carried out in the presence of solvents such as ether, dichloromethane, chloroform, DMF, DMSO and the like. The reaction may be carried out in the range of xe2x88x9240xc2x0 C. to 160xc2x0 C. The duration of the reaction may range from 1 to 6 h.
In another embodiment of the invention there is provided a process for the p reparation of the compound of formula (I) where R4 represents halogen and other symbols are as defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises: reacting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier with suitable halogenating agent to produce a compound of formula (I), where R4 represents halogen atom such as fluorine, chlorine, bromine or iodine.
The reaction of compound of formula (I) where R4 represents hydrogen with halogenating agents, to produce a compound of formula (I) where R4 represents halogen may be carried out in the presence of reagents such as bromine trifluoride, N-bromosuccinimide-hydrogen fluoride (NBS-HF), cobalt (III) fluoride, lithium fluoride, potassium fluoride, sodium fluoride, cesium fluoride, potassium iodide, sodium iodide, iodine, iodine cerium (IV) ammonium nitrate, N-bromosucinimide, (NBS), N-chlorosucinimide (NCS), N-iodosucinimide (NIS), bromine, chlorine, POCl3, PCl3, PBr3 or SOCl2. The reaction may be carried out in the presence of solvents such as DCM, CHCl3, benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof. The temperature and duration of the reaction may be maintained in the range of xe2x88x9280 to 32xc2x0 C. and 3 to 48 h respectively.
In another embodiment of the present invention there is provided a novel intermediate of formula (X) 
where R1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl; R4 represents hydrogen; P1 and P2 may be same or different and independently represent trityl, t-butyldimethylsilyl, pivaloyl and the like, or esters such as acetate, propionate, benzoate and the like, or P1 and P2 together represent methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like.
The present invention also provides a process for the preparation of the compound of formula (X), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups using conventional methods to produce a compound of formula (VIII), 
where R4 represents hydrogen; P1 and P2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like,
(ii) reacting the compound of formula (VIII) defined above with compound of formula (IX)
R1xe2x80x94Lxe2x80x83xe2x80x83(IX)
where R1 and L have the meanings given above to produce a compound of formula (X), 
where R1, R4, P1 and P2 are as defined earlier.
The protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like. The reaction may be carried out in the presence of a suitable catalyst such as SOCl2, H2SO4, HClO4, pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like. The reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h. The reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In yet another embodiment of the present invention there is provided a novel intermediate of formula (XI) 
where R1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl and R4 represents hydrogen.
The present invention also provides a process for the preparation of the compound of formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups using conventional methods to produce a compound of formula (VIII), 
where R4 represents hydrogen; P1 and P2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like,
(ii) reacting the compound of formula (VIII) defined above with compound of formula (IX)
R1xe2x80x94Lxe2x80x83xe2x80x83(IX)
where R1 and L have the meanings given above to produce a compound of formula (X), 
where R1, R4, P1 and P2 are as defined earlier,
(iii) deprotecting the compound of formula (X) by conventional methods to produce a compound of formula (XI), 
where R1 and R4 have the meanings given above.
The protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like. The reaction may be carried out in the presence of a suitable catalyst such as SOCl2, H2SO4, HClO4, pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like. The reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h. The reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
The deprotection of a compound of formula (X) to produce a compound of formula (XI) may be carried out using deprotecting agent such as acetic acid, hydrochloric acid, formic acid, trifluoroacetic acid and the like. The reaction may be carried in the presence of suitable solvent such as water, THF, dioxane, DCM, CHCl3, methanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
It is appreciated that in any of the above-mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
The compound of formula (I) when produced through an intermediate compound, conventional functional group transformations such as hydrolysis, reduction or oxidation may be carried out.
For example, the compound of formula (I) where R1, R2 or R3 are multi substituted and the two substituents may form a linking group xe2x80x94Xxe2x80x94(CR11R12)nxe2x80x94Yxe2x80x94, which may be converted to a compound of formula (I), where R1, R2 or R3 are multisubstituted and the substituents are independent.
The pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I), formula (X) or formula (XI) wherever applicable with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, tromethamine, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
The stereoisomers of the compounds of formula (I), formula (X) and formula (XI) forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al. in xe2x80x9cEnantiomers, Recemates and Resolutionxe2x80x9d (Wiley Interscience, 1981).
Various polymorphs of compound of general formula (I), formula (X) and formula (XI) forming part of this invention may be prepared by crystallization of compound of formula (I), formula (X) or formula (XI) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray data or such other techniques.
Pharmaceutically acceptable solvates of compounds of formula (I), formula (X) and formula (XI) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol etc., preferably water and recrystallizing by using different crystallization techniques.
The present invention also envisages pharmaceutical compositions containing compounds of the formula (I), formula (X), formula (XI), or their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with the usual pharmaceutically employed carriers, solvents, diluents and other media normally employed in preparing such compositions.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition may be pharmaceutically acceptable carriers, diluents or solvents and also contain other active ingredients.
The compounds of the formulae (I), (X) and (XI) as defined above are clinically administered to mammals, including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.01 to about 100 mg/kg body weight of the subject per day or preferably about 0.01 to about 30 mg/kg body weight per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.